A Total Bitch

Just to be clear I’m talking about a dog, a female dog, the one that is the subject of this article and the occurrence of probably the rarest and most unusual form of endometriosis I’ve ever seen.

We know that endometriosis can occur in some strange places, like in the brain or in the heart, or in some animals you wouldn’t expect, like monkeys, or in some people you wouldn’t expect, like men or very young children, but this is a stand-out case.

There are several reasons this case stands out so much to me. Firstly is that, looking at all the other odd occurrences of endo, whilst they are indeed odd, they are not entirely unforeseen. For example, endo occurs in humans, so to find it other parts of the human body apart from near the reproductive organs and to find it in young girls or men is weird, but not totally irrational. By the same logic, because we are so closely related to primates genetically, it is not unexpected that some species of ape or monkey will have endometriosis too. What is unexpected though is endo in an animal very dissimilar to humans and one that, by all accounts, has never been shown to have endo and shouldn’t be able to have it.

To summarise this case, an 11 year old female German Shepherd was brought to a vet in Brazil, but died unexpectedly during an examination. Upon dissection the vets found a large growth behind the uterus and ovaries which they later identified as an endometrioma, a large cystic growth filled with solid tissue and blood. Endometriomas are cysts where the outer layer is made up of tissue resembling the normal endometrium and is filled with blood that can become broken down to a brown fluid – giving rise to the name ‘chocolate cyst’. Endometriomas commonly arise in the ovary in women, but can occur in other places like behind the uterus and on the ligaments that hold the uterus in place.

Why would we not expect to see endometriosis in dogs? Mainly because the reproductive system of a dog is very different to that of a human. Dogs do not have a menstrual cycle like humans, they have an estrous cycle and while the hormonal changes across the estrous cycle can be seen as similar to the menstrual cycle, the physical changes are quite different and the time scales between the stages of different cycles vary significantly. One of the most important examples is that if the dog doesn’t become pregnant, the endometrium will be reabsorbed by the uterus, whereas in human the endometrium is shed during menses. This raises the question of how the endometrioma appeared.

For a long time now it has been suggested that endometriosis arises from endometrial cells shed during menses passing backwards through the fallopian tubes and out into the pelvic cavity, where they implant and grow into endometriotic lesions. This is a process termed ‘retrograde menstruation’ and is favoured by many (but not me) as the best explanation of the origin of endometriosis. How then could we have an endometrioma in an animal that doesn’t menstruate? A theory put forward many years ago, called coelomic metaplasia, suggested that certain forms of endometriosis arise from hormonal changes, which induce transformation of the thin layer of tissue that surrounds the reproductive organs (the coelomic mesothelium). This seems a logical explanation for endometriosis of the ovary as the ovaries produce high levels of estrogen. It also provides a decent explanation for the extremely rare instances of endometriosis in men, all of whom had been undergoing hormone therapy for prostate cancer.  The authors of this article also point out that tumour and other types of cysts derived from the coelomic mesothelium are fairly common in female dogs, meaning this could be another, overlooked type. Could this explain an endometrioma in a dog? Possibly, although the vets noted no hormonal imbalances in the dog and no pathology of the ovaries that would result in altered hormone production. One other discovery that may give a hint as to how this endometrioma arose was the presence of bundles of smooth muscle found in the cyst. Normally smooth muscle wouldn’t be found in an endometrioma, so its presence suggests not a simple endometrioma, but a uterus like mass. How this might come about is speculative, it could be a birth defect that was only diagnosed when it became serious.

A big question then is – how come this is the first case of an endometrioma being reported in dogs? Dogs are brought to the vet all the time, there are probably millions of dogs visits to vets every year, why is this the first case? The short answer to that is, I don’t really know. It may be that endometriomas are simply not recognised as endometriomas in dogs. In this case study the authors state “based solely on the macroscopic mass, especially the red color and the presence of cavities filled with coagulated blood, an initial diagnosis of hemangiosarcoma was made in this dog”. So it could be endometriomas are being mistaken for cancer in dogs, but I don’t know if microscopic analysis is routinely performed on dog tumours so it’s hard to tell if this is the case.

The incidence of endometriosis in non-human species is an area that has received very little attention save for a few species of monkey used in lab experiments. It may be that endometriosis is extremely rare in non-human species, or it is underdiagnosed either due to lack of awareness or microscopic analysis of animal tumours isn’t a routine procedure. Either way it would appear endometriosis is not a uniquely human concern.  

Highlights from WCE 2014 - Part 3

Carrying on with our WCE 2014 highlights, let’s have a look at some of the research into fertility issues and endometriosis. Reduced fertility is one of the major problems faced by women with endometriosis, yet there are still many mysteries surrounding how endometriosis affects fertility.

In order to shed at least some light on the issue an Italian research team investigated how ovarian endometriosis (endometrioma) can affect the viability of ovarian follicles in women undergoing IVF. What they found was that follicles closer to endometrioma showed higher levels of iron. Iron, of course, is important for your body but in endometriomas iron accumulates in high amounts, probably due to blood filling the inside of the cyst. These high levels of iron can be toxic to anything close by, in this case, ovarian follicles. This leads to impaired development of the follicle and perhaps partly explains why so many women with endometrioma/s find it hard to conceive.

If you have an endometrioma, chances are you’ll want surgery to remove it, but you’ll also want to know what the risk of recurrence is and what factors influence that risk. A team from Brazil looked at the records from 202 women undergoing laparoscopic excision of endometrioma between and 2003-2012 and analysed those records to see what influenced endometrioma recurrence. They found that the overall rate of endometrioma recurrence was 16.4% and that factors such as age, race, symptoms, exercise, number of children and type of surgical procedure had no effect on recurrence rates. However, they found that having a cyst larger than 6cm (which is pretty large) and stopping medical therapy after surgery significantly increased the chance of endometrioma recurrence (although the abstract didn’t specify which medical therapy was used). Because of the side effects associated with some of the medical treatments for endometriosis, it is unsurprising some women need to stop treatment. However, if stopping treatment means an increased risk of disease recurrence, then more work needs to be put into ensuring other, more tolerable medical options are made available.

Speaking of IVF, some women who suffer with fertility issues may consider IVF as a means of conception. It is therefore important for women with endo to know if their condition may affect their IVF outcome. A group from France compared 291 women with endo to 1316 women without to see what the effects, if any, endo made to the delivery rates after undergoing IVF. What the researchers found was that, in the women who had good ovarian stimulation response and high quality embryos, the total cumulative successful delivery rate for fresh and frozen embryos was 52.3% for women with endo and 45.8% for women without. Although women with endo had lower rates of good ovarian stimulation, the overall outcome was no different between women with and without endo. This suggests that having endo (regardless of stage) may not impact the success of IVF.

Although it appears that endo doesn’t affect the success of IVF, it would still be good to have some way of improving IVF outcomes. A group from New Zealand has been conducting a randomised, controlled trial to see if a drug called Lipiodol has any benefit on IVF outcomes, as their initial tests showed this treatment improved the fertility of women with endo much more than women who couldn’t conceive but didn’t have endo. Lipiodol can normally be used for hysterosalpingography (a procedure used to determine the shape of the uterus and fallopian tubes) and is injected into the uterine cavity so comes into contact with the endometrium. The authors of this study think that Lipiodol ‘bathes’ the endometrium, making it more receptive to a fertilized egg. Their results are still very preliminary so should be met with cautious optimism, but are still encouraging. The women who received IVF alone achieved a live delivery in 22.7% of cases, but the women who had Lipiodol treatment plus IVF achieved a live delivery 43.8%. These results are encouraging, but we’ll have to wait until the clinical trials have been completed and the results properly analyzed before drawing any firm conclusions.

Endometriosis Awareness Month - Part 2

Endometriosis is a disease of many facets, pain being the most obvious and prevalent one. However there are other aspects of the disease that have a significant impact on the sufferer that receive less attention. One such aspect is infections.

Despite studies showing that women with endometriosis are more commonly affected by respiratory tract infections and recurrent vaginal infections, there is relatively little investigation into the reason behind this observation.  Some point to alterations in the immune system of women with endo that may reduce the body’s defence against to infection. Other studies found the menstrual blood of women with endo has higher levels of factors which promote the growth of certain bacteria.

Whatever the cause may be, it is still an area if ongoing interest and there have been two studies published very recently investigating different types of infection in women with endo.

The first study, from Japan, was designed to see if there is any association between endometriosis and endometritis. Endometritis is often confused for endometriosis, if only for the similarity of the words, but they are in fact very different conditions. Endometritis is an inflammation of endometrium, which can be due to infection by a number of different bacteria and, although generally may not present with any symptoms, it can cause lower abdominal pain, vaginal discharge and fever. 

This study took 34 women with endometriosis and 37 without endometriosis, who were undergoing hysterectomy, and analysed their endometrium for signs of endometritis. Most of the characteristics of the women (such as age/BMI/menstrual cycle length) didn’t significantly vary. However, adenomysosis was found in 47% of the women with endo, but only 8% of the women without endo. In addition, fibroids were found in 68% of the women with endo and 95% of the women without (but we must remember these were women scheduled for hysterectomy, so it would be expected to see high percentages of uterine conditions).

After analysing the endometrium the investigators found there was a significant association between having endometriosis and chronic endometritis. 53% of the women with endo were also diagnosed with endometritis, but only 27% of the women without endo had endometritis.

Breaking endometriosis cases down by stage also yielded some interesting results, below is what the investigators found

Endometriosis Stage	Percentage of women with endometritis
Stage I	40%
Stage II	50%
Stage III	70%
Stage IV	47%

The increase in endometritis as stage increases (up to stage III) is an interesting find, but the number of women used for this part of the analysis was very small, which might make the results seem more significant than they would be if you repeated this study with a larger number of patients. It would have been interesting to see if endometritis was associated with any specific symptoms of endometriosis (such as dysmenorrhea, chronic pelvic pain, subfertility etc) as stage of disease is not really related to severity of symptoms.

When discussing their findings, the investigators suggested that endometritis in women with endometriosis may not necessarily be due to infection. Endometritis was defined, in this instance, by the presence of plasma cells (a type of white blood cell) in the endometrium not the direct observation of bacteria. The endometrium of women with endometriosis has a number of alterations; so there may be some factor produced by the endometrium of women with endo that causes these plasma cells to appear. It could even be that the cause of endometritis in women with endo lies outside the uterus. The pelvic environment is linked to the uterus via the fallopian tubes, therefore it is possible that some inflammatory factor produced by endometriosis might travel into the uterus and cause the changes that were observed in this study. As is usually the case with a new discovery, it raises more questions than it answers, but this certainly opens the door to new areas of research.

Onto the next study then, from Israel, which investigated pelvic inflammatory disease (PID) in women with endometriosis. PID is one of the common misdiagnoses of women with endo as the symptoms (such as pelvic pain, painful sex, heavy, painful periods) are quite similar to those of endo, though PID may not have any obvious symptoms. PID is caused by a bacterial infection in the vagina or cervix, which then spreads up into the uterus or fallopian tubes, it can be diagnosed with a cervical swab and is usually successfully treated with a course of antibiotics.

The investigators reviewed medical records of women admitted to their hospital, between 2008 and 2011, for either PID or tubo-ovarian abscess (TOA, basically an abscess of the fallopian tube or ovary) and divided them into two groups. Group 1 was 21 women who also had stage III-IV endometriosis and group 2 was 127 women without endometriosis.

Unsurprisingly when the records were reviewed the investigators found that women in group 1 had much more fertility treatments or IVF than those in group 2. What was surprising was the way PID or TOA affected women with endo. In this study, women with endo experienced significantly more severe PID infections which required a longer hospital stay, a higher rate of failure to respond to antibiotics and, in some cases, surgical intervention.

The authors point out that PID and TOA seemed to be more likely to develop in women with endo after undergoing fertility treatments, in particular IVF. This may have something to do with the association of ovarian endometriotic cysts (endometrioma) with TOA. The authors suggest that the blood and fluid that builds up inside an endometrioma might serve as a kind of ‘growth serum’ for bacteria and if a cyst is ruptured (either naturally or is pierced during surgery or oocyte retrieval) it could potentially spread infection through the reproductive organs.

It would be interesting to repeat this study with more women of stage I-II endometriosis to see if the association holds, or whether severe PID infections are only more common in women with stage III-IV disease who have recently undergone fertility treatment. Obviously it would be beneficial to follow this up with studies into how to prevent severe PID in women with endometriosis or how to better treat it. The authors found that 76% of the women with endometriosis had already undergone at least one surgery which didn’t seem to decrease their risk of developing PID. Perhaps modifying surgical approaches to include cleaning of the pelvic area or treating women with ruptured endometrioma with antibiotics after surgery as a precaution may help? Again there is still much work to be done before we have some answers and better clinical care for women with endo can be achieved, but now the problem has been highlighted, we can work towards a solution.

As an aside, a fellow endo blogger and activist from Brazil who writes the Endometriose e Eu blog is currently in the running to win award for her writing. It would be awesome if anyone reading this could vote for her blog to help put endo in the spotlight in Brazil. Simply go to this page and in the top right you should see boxes to vote by email and Facebook, obrigado!

Nuking Endometriosis

Endometriosis is a notoriously difficult condition to treat; there are the drug therapies, but they are often hit or miss and can come with a plethora of unpleasant side effects. Then there is surgical treatment, which has the advantage of a better rate of relieving symptoms but it cannot guarantee the disease won’t return later, which may result in more surgery. Either way there always seems some medical or surgical options available, but what happens when the options run out?

A recent case report from Yamagata University Hospital in Japan starts with the authors finding themselves in that very situation. They were presented with a 47 year old woman with endometriosis (specifically chocolate cysts on both ovaries) who also experienced abnormal vaginal bleeding to the point where she was requiring blood transfusions. Medical therapy for her endometriosis didn’t help so the next logical step would be surgery, right? Not in this case, unfortunately the woman in question also suffered from idiopathic thrombocytopenic purpura (mercifully shortened to ITP) which means she has an abnormally low red blood cell count, making surgical intervention extremely dangerous.

Her doctors clearly weren’t in the giving up mood and in an inspired move decided maybe radiotherapy was the answer. You’ve probably heard of radiotherapy before but it’s normally used to treat tumours. In this case though the doctors elected to create a ‘radiation induced menopause’ by targeting the woman’s ovaries and endometrium with controlled doses of radiation. The authors report that after this course of radiotherapy the woman’s symptoms had abated and the abnormal vaginal bleeding had stopped.

Overall this was an extreme but successful treatment option for this patient. It’s not the first instance of radiotherapy for endometriosis either, but it is incredibly rare that this method is employed, mainly because it’s unusual for a patient to not respond to medical therapy and be unable to have surgical treatment. Also a major drawback is the irreversible loss of all ovarian function, so it would not be recommended for anyone who ever wants a family and hormone replacement therapy would probably be needed to control menopausal symptoms.  

How much endometriosis?

When we think of endometriosis, size does not usually factor into our concerns. If you look at and endometriotic implant such as these ones, which are between 1 and 5mm in size, they typically tend to be quite small. In fact some patches of endometriosis are so small they cannot be seen with the naked eye. The only exceptions are endometriomas (or chocolate cysts), which are ovarian cysts of varying size that are caused by endometriosis. Endometriomas can range from being small (like the size of a marble), to being quite large (like the size of a grapefruit). Generally any endometriomas in excess of 5cm requires surgical attention.

Spare a thought then for the woman who is the subject of the following case study published in the Journal Clinical and Experimental Obstetrics and Gynaecology. The report states that a 51 year old, morbidly obese woman was admitted to hospital with anaemia, respiratory problems and kidney failure, so her story doesn’t start well. Further investigation revealed a large mass in her abdomen that had to be surgically removed. Analysis of this mass found it to be an astounding 64Kg (that’s just over 10 stone) of endometrioma.

I’m not sure but I think that’s some sort of record.